The prevalence of heroin use has been increasing. However, the availability of efficacious treatments is limited, and relapse rates remain high. The development of more effective pharmacotherapies that reverse the physiologic effects of opioid dependence and prevent relapse to heroin use remains a priority. This application for a mentored research career award aims to enhance the research skills of Adam Bisaga, MD, by focusing on a systematic laboratory and clinical evaluation of memantine, an NMDA antagonist, for the treatment of opioid dependence. Dr. Bisaga, a Board Certified psychiatrist, is a research fellow in the Division on Substance Abuse at Columbia University. As a psychiatric resident and fellow, Dr. Bisaga has been exploring the theoretical basis for the clinical use of NMDA antagonists in the treatment of addictions and has collected pilot data using memantine to treat the opioid abstinence syndrome. In the next several years, he plans to carry out studies that would systematically evaluate the efficacy of memantine for opioid dependence. Two aspects of pharmacotherapy will be addressed: detoxification and relapse prevention. This novel approach to treatment will be initially evaluated using a laboratory model, and will be followed by a controlled clinical trial. Unique expertise and resources available at the Division on Substance Abuse make possible comprehensive training in such translational research. Under the sponsorship and guidance of Dr. Marian Fischman, together with the resources available at Columbia University, Dr. Bisaga will be able to achieve his long-term career goal of becoming a clinical research scientist with expertise in multiple approaches in addiction research and medication development. His training plan includes an extensive program of individualized instruction by major experts in the field, both at Columbia and elsewhere, in addition to formal course work. Training is planned specifically in the following areas: methods of new medications development for opioid dependence, including methodology and logistics of conducting clinical treatment trials; methodology and ethics of conducting research with opioids in the human laboratory; psychology of learning and conditioned responses; psychotherapy with substance abusers; integration of psychosocial interventions into medication treatment trials, and biostatistics. The research plan specifically includes the following: a laboratory study examining the effect of memantine on naloxone-precipitated opiate withdrawal, followed by a controlled clinical opioid detoxification trial comparing memantine with clonidine; a laboratory study of the effects of memantine pretreatment on cue-induced opioid craving in opioid-dependent subjects maintained on naltrexone; and a placebo-controlled trial of adjunctive memantine in the population of patients receiving naltrexone and cognitive behavioral therapy for opioid addiction. Taken together, the proposed plans will provide Dr. Bisaga with the opportunity to receive state-of-the-art training and research experience that will enable him to become an independent researcher in the field of addiction psychiatry.